Objective Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent for coronavirus disease 2019(COVID-19),is responsible for the recent global pandemic.As there are no effective drugs or vaccine...Objective Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent for coronavirus disease 2019(COVID-19),is responsible for the recent global pandemic.As there are no effective drugs or vaccines available for SARS-CoV-2,we investigated the potential of flavonoids against SARS-CoV-2 main protease 6YNQ.Methods In silico molecular simulation study against SARS-CoV-2 main protease 6YNQ.Results Among the 21 selected flavonoids,rutin demonstrated the highest binding energy(−8.7 kcal/mol)and displayed perfect binding with the catalytic sites.Conclusions Our study demonstrates the inhibitory potential of flavonoids against SARS-CoV-2 main protease 6YNQ.These computational simulation studies support the hypothesis that flavonoids might be helpful for the treatment of COVID-19.展开更多
O-GlcNAc transferase （OGT） is one of essential mammalian enzymes, which catalyze the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine （UDP-GlcNAc） to hydroxyl groups of serines and threonines （Ser/Thr...O-GlcNAc transferase （OGT） is one of essential mammalian enzymes, which catalyze the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine （UDP-GlcNAc） to hydroxyl groups of serines and threonines （Ser/Thr） in proteins. Dysregulations of cellular O-GlcNAc have been implicated in diabetes, neurodegenerative disease, and cancer, which brings great interest in developing potent and specific small-molecular OGT inhibitors. In this work, we performed virtual screening on OGT catalytic site to identify potential inhibitors. 7134792 drug-like compounds from ZINC （a free database of commercially available compounds for virtual screening） and 4287550 compounds generated by FOG （fragment optimized growth program） were screened and the top 116 compounds ranked by docking score were analyzed. By comparing the screening results, we found FOG program can generate more compounds with better docking scores than ZINC. The top ZINC compounds ranked by docking score were grouped into two classes, which held the binding positions of UDP and GlcNAc of UDP- GlcNAc. Combined with individual fragments in binding pocket, de novo compounds were designed and proved to have better docking score. The screened and designed compounds may become a starting point for developing new drugs.展开更多
Triple-negative breast cancer is an aggressive subtype that frequently develops resistance to chemotherapy. It is expected to develop new anti-tumor drugs through targeting the structure of G-quadruplexes of the genes...Triple-negative breast cancer is an aggressive subtype that frequently develops resistance to chemotherapy. It is expected to develop new anti-tumor drugs through targeting the structure of G-quadruplexes of the genes associated with this tumor. In this work, by targeting the 21-mer telomere G-quadruplex structure, compounds VB07 and VC02 were identified to stabilize the telomere G-quadruplex through structure-based high-throughput virtual screening. Cell cytotoxicity assay showed that VB07 and VC02 exhibited inhibitory effect on triple-negative breast cancer cells at the concentration of 5 μM. This study showed that structure-based high-throughput virtual screening was able to successfully identify the proper compounds targeting the telomere G-quadruplex, which exhibited inhibitory effects against the triple-negative breast cancer cells.展开更多
文摘Objective Severe acute respiratory syndrome coronavirus 2(SARS-CoV-2),the causative agent for coronavirus disease 2019(COVID-19),is responsible for the recent global pandemic.As there are no effective drugs or vaccines available for SARS-CoV-2,we investigated the potential of flavonoids against SARS-CoV-2 main protease 6YNQ.Methods In silico molecular simulation study against SARS-CoV-2 main protease 6YNQ.Results Among the 21 selected flavonoids,rutin demonstrated the highest binding energy(−8.7 kcal/mol)and displayed perfect binding with the catalytic sites.Conclusions Our study demonstrates the inhibitory potential of flavonoids against SARS-CoV-2 main protease 6YNQ.These computational simulation studies support the hypothesis that flavonoids might be helpful for the treatment of COVID-19.
文摘O-GlcNAc transferase （OGT） is one of essential mammalian enzymes, which catalyze the transfer of N-acetylglucosamine from UDP-N-acetylglucosamine （UDP-GlcNAc） to hydroxyl groups of serines and threonines （Ser/Thr） in proteins. Dysregulations of cellular O-GlcNAc have been implicated in diabetes, neurodegenerative disease, and cancer, which brings great interest in developing potent and specific small-molecular OGT inhibitors. In this work, we performed virtual screening on OGT catalytic site to identify potential inhibitors. 7134792 drug-like compounds from ZINC （a free database of commercially available compounds for virtual screening） and 4287550 compounds generated by FOG （fragment optimized growth program） were screened and the top 116 compounds ranked by docking score were analyzed. By comparing the screening results, we found FOG program can generate more compounds with better docking scores than ZINC. The top ZINC compounds ranked by docking score were grouped into two classes, which held the binding positions of UDP and GlcNAc of UDP- GlcNAc. Combined with individual fragments in binding pocket, de novo compounds were designed and proved to have better docking score. The screened and designed compounds may become a starting point for developing new drugs.
基金National Natural Science Foundation of China(Grant No.31701791,21732002,31672558 and 21502060)Huazhong Agricultural University Scientific&Technological Self-innovation Foundation(Grant No.2662017PY113,2015RC013 and 2662015PY208)Open fund of The State Key Laboratory of Bio-organic and Natural Products Chemistry,CAS(Grant No.SKLBNPC16343)。
文摘Triple-negative breast cancer is an aggressive subtype that frequently develops resistance to chemotherapy. It is expected to develop new anti-tumor drugs through targeting the structure of G-quadruplexes of the genes associated with this tumor. In this work, by targeting the 21-mer telomere G-quadruplex structure, compounds VB07 and VC02 were identified to stabilize the telomere G-quadruplex through structure-based high-throughput virtual screening. Cell cytotoxicity assay showed that VB07 and VC02 exhibited inhibitory effect on triple-negative breast cancer cells at the concentration of 5 μM. This study showed that structure-based high-throughput virtual screening was able to successfully identify the proper compounds targeting the telomere G-quadruplex, which exhibited inhibitory effects against the triple-negative breast cancer cells.
